Enzyme That Protects Chromosomes from Oxidative Damage and Shortening

When cells divide, they pack up all of their genetic material in the
tightly wrapped chromosomes. The ends of our chromosomes have a unique
structure, named a telomere.

Replication of telomeres requires
specialized mechanisms, which adult organisms only have in a small
number of cells. This means that chromosomes become shorter over time,
limiting the lifespan of cells and contributing to aging. Telomeres are
also very sensitive to oxidative damage, which affects their ability to
replicate.

EPFL scientists have identified a protein that caps chromosomes
during cell division and protect them from oxidative damage and
shortening, which are associated with aging and cancer. The discovery, published in Cell Reports, could have significant implications for how we could treat cancer and other age-related diseases in the future.

‘The protein, called Peroxiredoxin 1 (PRDX1), caps chromosomes during cell division and protects them from oxidative damage and shortening. This may have implications for how to treat cancer and age-related diseases.’

Division, damage, and shortening

Precise transmission of the genome from a cell to its progeny is
vital to maintain its characteristics and for the health of the entire
organism. Our genome is constantly subjected to damage from
environmental factors such as sunlight and oxygen radicals, which are
by-products of our normal metabolic functions. As such, oxidative damage
is a constant threat to all life on Earth.

Cells have evolved numerous antioxidative defenses, but some parts
of the cell, like the chromosome tips, the telomeres, are particularly
vulnerable to oxidative damage. Telomeres are sequences of repetitive
nucleotides at each end of a chromosome. Their role is to protect that
end from damage or from fusing with other chromosomes, which would be
catastrophic for the cell.

In most adult tissues, every time it divides,
its chromosomes shorten a little in length; eventually, the telomeres
shorten so much that the end of the chromosome becomes exposed, which
causes either the death of the cell or an irreversible block to further
divisions. This process is accelerated by oxidative damage. The
prevailing theory of aging, as well as cancer, cites a central role for
oxidative damage of the telomeres in these processes.

An enzyme that protects telomeres

Chromosomes are made up of DNA that is tightly wound up around
specialized proteins. The labs of Joachim Lingner and Viesturs Simanis
at EPFL analyzed the protein make-up of telomeres across the entire cell
cycle to better understand how oxidative damage affects telomeres
during division.

The researchers used a number of molecular biology techniques,
including a relatively new one called QTIP, which labels various
proteins in chromosomes so that researchers can compare and identify
quantitative differences between the protein composition of telomeres in
various phases of the life cycle.

The study identified an enzyme called Peroxiredoxin 1 (PRDX1). It
functions as an antioxidant enzyme, meaning that it is used by cells to
mitigate the effects of oxidative damage.

Using QTIP, the researchers found large amounts of PRDX1 on
telomeres during two phases of the cell cycle: the phase when the cells
synthesizes new DNA and duplicates its genetic material (S-phase), and
during the immediately following phase (G2), when the cell grows in size
just before it begins dividing.

Using genetic techniques, the scientist removed PRDX1 from the
cells, and found that the telomeres were even more susceptible to
oxidative damage. This means that PRDX1 plays an antioxidative role that
protects telomeres.

In addition, the researchers were able to shed some light onto how
oxidative damage affects telomeres. When they incorporated an
oxidatively damaged nucleotide into telomeres, they found that the
chromosome stopped growing. The reason is that the enzyme called
telomerase that builds chromosomes by elongating them abruptly abandoned
the process when it encountered the damaged nucleotide. As cancer cells
require telomerase for survival this finding may open up novel avenues
for attacking this enzyme in cancer.

"Our study links oxidative damage and telomeres, both of which have
been previously linked to aging and cancer," says Joachim Lingner. In
addition to these, oxidative damage of telomeres is also connected to
cardiac failure and muscular dystrophy. Having identified PRDX1,
Lingner's lab will now try to determine if there are other antioxidant
enzymes that can protect telomeres: "We expect that further studies of
this problem will provide insights that help us understand mechanisms of
cancer development, aging and inherited disease."

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